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An enhanced immune response in mice lacking the transcription factor NFAT1
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Transcription factors of the NFAT family are thought to play a major role in regulating the expression of cytokine genes and other inducible genes during the immune response. The role of NFAT1 was investigated by targeted disruption of the NFAT1 gene. Unexpectedly, cells from NFAT1-/- mice showed increased primary responses to Leishmania major and mounted increased secondary responses to ovalbumin in vitro. In an in vivo model of allergic inflammation, the accumulation of eosinophils and levels of serum immunoglobulin E were increased in NFAT1-/- mice. These results suggest that NFAT1 exerts a negative regulatory influence on the immune response.
The response of the immune system to antigen is coordinated by an interacting network of transcription factors that dictate expression of effector proteins such as cell surface receptors and cytokines (1, 2). The recently identified NFAT family of transcription factors is thought to play a critical role in this process (3). NFAT DNA binding activity has been detected in nuclear extracts of antigen-stimulated T cells, B cells, mast cells, and natural killer (NK) cells (4, 5), and NFAT binding sites have been identified in the promoter and enhancer regions of many genes encoding immunoregulatory proteins (4, 6). The NFAT family comprises several structurally related proteins that are encoded by at least four distinct genes (1-9). The best characterized member of the NFAT family, NFAT1 (formerly NFATp) (7, 8), is expressed constitutively as a cytoplasmic phosphoprotein in resting immune system cells (10, 11); upon stimulation, it is rapidly dephosphorylated and translocated to the nucleus by way of a calcium-calcineurin-dependent pathway (11, 12). Individual NFAT proteins may be able to substitute for one another in regulating expression of certain target genes, because each can bind cooperatively with Fos and Jun to DNA and activate transcription of the interleukin-2 (IL-2) promoter in transient transfection assays...